Changes in blood flow distribution during the perinatal period in fetal sheep and lambs.

We have measured total blood flows and blood flows per 100 g tissue to major tissues at 120 and 140 days gestation in fetal sheep and at 3 and 21 days of age in lambs (gestation period = 144 +/- 2 days). Between 120 and 140 days gestation, flow per 100 g tissue increased by 74, 150, and 317% in the renal, intestinal, and hepatic arterial beds, but no further significant change in flow was observed at 3 or 21 days postpartum. Blood flows per 100 g to cerebral hemispheres and cerebellar tissues also increased dramatically during late gestation (142 and 121%, respectively), but declined sharply by 3 days postpartum (73 and 75%, respectively). Brain blood flows at 21 days postpartum remained substantially below late gestational levels. Adrenal blood flows per 100 g more than doubled during late gestation, fell by more than half at birth, and only partially recovered by 21 days of age. Blood flows to carcass tissues did not change in late gestation, fell at birth, then partially recovered. Pre- and post-natal increases in brain blood flows were almost entirely attributable to increased perfusion rather than tissue growth, whereas large perinatal increases in flow to the diaphragm paralleled tissue growth. Tissue growth and increased perfusion per 100 g contributed almost equally to increased blood flows to kidneys postnatally, and to adrenal glands and the gastrointestinal tract prenatally.     

Effects of severe reduction in maternal placental blood flow on blood flow distribution in the sheep fetus

To test the hypothesis that fetal lambs are able to maintain oxygen delivery to myocardial, brain and adrenal tissues during reduction in uterine blood flow to 25% of control, we performed experiments on five ewes and their fetuses. A snare occluder was placed around the maternal common hypogastric artery and catheters were placed for measurement of blood pressures, flows, blood gas tensions, pH and oxygen content. After a five day recovery period, control measurements were made. The snare occluder was then closed until the artery was fully occluded. The arterial occlusion caused uteroplacental blood flow to fall to 32 +/- 4% and maternal placental blood flow to fall to 25 +/- 3% of control values. This level of asphyxia was maintained for 19 +/- 3 minutes, when maternal and fetal blood flows were measured again. In response to occlusion, fetal ascending aortic PO2 fell from 21 +/- 2 (SEM) to 13 +/- 2 mmHg (P less than or equal to 0.01), oxygen content from 4.3 +/- 0.3 to 1.4 +/- 0.2 mM (P less than or equal to 0.01) and pH from 7.37 +/- 0.01 to 7.21 +/- 0.05 (P less than or equal to 0.01). PCO2 rose from 48 +/- 1 to 62 +/- 3 mmHg (P less than or equal to 0.01). Fetal arterial blood pressure increased from 51 +/- 3 to 61 +/- 3 mmHg (P less than or equal to 0.001) and heart rate decreased from 172 +/- 10 to 104 +/- 4 beats.min-1 (P less than or equal to 0.01). The heart, brain and adrenals showed vasodilation in response to the asphyxic stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ovine fetal electrocortical activity and regional cerebral blood flow

Fetuses of 12 near-term sheep were prepared for microsphere determination of cerebral blood flow. Experiments were performed 5 days postsurgery. The regional blood flows were measured in successive high (HV), low (LV) and high voltage electrocorticographic states. Comparisons were made between the observations made in the LV and averaged flanking HV cycles. Total cerebral blood flow was 95 +/- 8, 119 +/- 11 and 100 +/- 9 ml/min/100 g in HV, LV and HV, respectively. Low voltage electrocortical activity increased average cerebral blood flow by 22% (P less than 0.01). Significant changes were seen in all regions except the occipital cortex. The maximum change was observed in the thalamus in which the flows were 152 +/- 23, 243 +/- 35 and 138 +/- 20 ml/min/per 100 g tissue, respectively. The increase was 68% (P less than 0.001). The percent changes seen in the cerebrum are as follows: Frontal grey + 18%, frontal white + 22%, parietal white + 22%, temporal + 18%. A + 17% change was seen in the cord (P less than 0.03). It is concluded that in low voltage electrocortical activity all of the brain, except the occipital region, shows an increase in cerebral blood flow. This is probably secondary to a variance in cerebral activity. This preparation may be useful in localizing function in the fetal brain.     

Effects of exercise and heat stress on regional blood flow in pregnant sheep

Radioactive microspheres were used to measure cardiac output and blood flow to most major tissues, including those in the pregnant uterus, in late-pregnant ewes at rest and during treadmill exercise (approximately 3-fold increase in metabolic rate for 30 min) in thermoneutral (TN) (dry bulb temperature (Tdb) = 13 degrees C, wet bulb temperature (Twb) = 10 degrees C) and mildly hot (MH) (Tdb = 40 degrees C, Twb = 27 degrees C) environments. Exercise caused major increases in blood flow to respiratory muscles, nonrespiratory limb muscles, and adipose tissue, and flow was decreased to some gastrointestinal tissues, spleen, pancreas, and to placental and nonplacental tissues in the pregnant uterus. Heat exposure had relatively little effect on these exercise-induced changes, except that flow was further increased in the respiratory muscles. Results are compared with those of a similar study on nonpregnant sheep in which changes in muscle, skin, and visceral flows during exercise were attenuated by heat exposure. It is suggested that redistribution of blood flow from the pregnant uterus, which in resting ewes took 22% of cardiac output, is a significant buffer against the potentially deleterious effects of combined exercise and heat stress on blood flow to exercising muscles and thermoregulatory tissues.     

Effects of reducing uterine blood flow on fetal blood flow distribution and oxygen delivery.

We examined the effect of graded reduction in uterine blood flow on distribution of cardiac output and oxygen delivery to fetal organs and venous blood flow patterns in 9 fetal sheep using the radionuclide-labeled microsphere technique. We reduced uterine blood flow in two steps, decreasing fetal oxygen delivery to 70% and 50% of normal, and compared the results with those from a similar study from our laboratory on graded umbilical cord compression. With 50% reduction in fetal oxygen delivery, blood flow and the fraction of the cardiac output distributed to the brain, heart, and adrenal gland increased and that to the lungs, carcass, skin, and scalp decreased. Oxygen delivery to the brain and myocardium was maintained, while that to the adrenal doubled, and that to the brain stem increased transiently. The decrease in oxygen delivery to both carcass and lower body segment correlated linearly with oxygen consumption (P less than 0.001). The proportion of umbilical venous blood passing through the ductus venosus increased from 44.6% to 53% (P less than 0.05). The preferential distribution of ductus venosus blood flow through the foramen ovale to the heart and brain increased, but that to the upper carcass decreased so that ductus venosus-derived blood flow to the upper body did not change. Hence, the oxygen delivered to the brain from the ductus venosus was maintained, and that to the heart increased 54% even though ductus venosus-derived oxygen delivery to the upper body fell 34%. Abdominal inferior vena caval blood flow and its contribution to cardiac output decreased, but the proportion of the abdominal inferior vena caval blood distributed through the foramen ovale also increased from 23.0 to 30.9%. However, the actual amount of inferior vena caval blood passing through the foramen ovale did not change. There was a 70% fall in oxygen delivery to the upper body segment from the inferior vena cava. A greater portion of superior vena caval blood was also shunted through the foramen ovale to the upper body, but the actual amounts of blood and oxygen delivered to the upper body from this source were small. Thus, graded reduction of uterine blood flow causes a redistribution of fetal oxygen delivery and of venous flow patterns, which is clearly different from that observed previously during graded umbilical cord occlusion.     

Effects of chronic reduction in uterine blood flow on fetal and placental growth in the sheep

Pregnancy is associated with a significant increase in uteroplacental blood flow (UBF), which is responsible for delivering adequate nutrients and oxygen for fetal and placental growth. The present study was designed to determine the effects of vascular insufficiency on fetal and placental growth. Thirty-nine late-term pregnant ewes were instrumented to investigate the effects of chronic UBF reduction. Animals were split into three groups based on uterine blood flow, and all animals were killed on gestational day 138. UBF, which began at 851 +/- 74 ml/min (n = 39), increased in controls (C) to 1,409 +/- 98 ml/min (day 138 of gestation) and in the moderately restricted (R(M)) group to 986 +/- 69 ml/min. In the severely restricted (R(S)) group, UBF was only 779 +/- 79 ml/min on gestational day 138. This reduction in UBF significantly affected fetal body weight with R(M) fetuses weighing 3,685 +/- 178 g and R(S) fetuses weighing 2,920 +/- 164 g compared with C fetal weights of 4,318 +/- 208 g. Fetal brain weight was not affected, whereas ponderal index was significantly reduced in R(M) (2.94 +/- 0.09) and R(S) fetuses (2.49 +/- 0.08) compared with the value of the C fetuses (3.31 +/- 0.08). Placental weight was also significantly reduced in the R(M) group, being 302 +/- 24 g, whereas the R(S) group placenta weighed 274 +/- 61 g compared with the C values of 414 +/- 57 g. Fetal heart, liver, lung, and thymus were all significantly smaller in the R(S) group. Thus the present study shows a clear relationship between the level of UBF and both fetal and placental size. Furthermore, the observation that fetal brain weight was not affected, whereas fetal body weight was significantly reduced suggests that this experimental preparation may provide a useful model in which to study asymmetric fetal growth restriction.     

Measurement of blood flow and oxygen consumption in the pelvic limb of fetal sheep

In order to determine blood flow and oxygen consumption in the pelvic limb of fetal sheep, we applied the Fick principle of measurement of oxygen consumption in seven paired experiments in seven fetal sheep under normal conditions and after treatment with pancuronium bromide. Catheterization procedures, which minimized interference with the study limb circulation, avoided changes of catheter tip position during fetal movements,n and prevented collateral circulation to and from tissues not located in the pelvic limb, were utilized. Blood flow through the external iliac artery was measured by means of a transit time ultrasonic method. Six sample sets for oxygen content were drawn from the external iliac artery and vein during 45-min control period and repeated after neuromuscular blockade. Normal oxygen consumption under these experimental conditions was determined to be 20.7 +/- 1.9 (mean +/- SEM) mumole.min-1.100 g-1. Neuromuscular blockade caused oxygen consumption to decrease significantly (P less than 0.01) by 12% to 18.1 +/- 2.1 mumole.min-1.100 g-1 and decreased the average coefficient of variation from 15 to 8%. The data demonstrate that spontaneous skeletal muscle activity accounts for a significant amount of oxygen consumption, the level of which can vary widely over brief periods of time. These results suggest that such tissues with significant spontaneous changes in metabolic activity require repeated blood flow measurements with simultaneous determination of substrate arteriovenous differences to best describe metabolism under normal conditions.     

Behavioral state transition and local cerebral blood flow in fetal sheep.

Local cerebral blood flow in four near term fetal sheep was evaluated continuously before and after natural alternations in fetal behavioral state. Measurements were made in fetuses several days following an aseptic surgery to place electrodes for behavioral state recordings as well as heated and reference thermojunctions in cortical and subcortical tissue. These thermojunctions were used to qualitatively assess local cerebral blood flow. The time of transition between rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS) was based on visual inspection of strip chart recordings of electrocortical, electroocular, and neck electromyographic activity and application of published criteria for their assessment. To confirm that transition had occurred, the amplitude of the spectrum of the electrocorticogram in one-third octave bands centered around 1 Hz and 20 Hz was measured before and after the transition point. Mean cerebral blood flow rose significantly by 24 s (P less than 0.05) after the transition from NREMS to REMS and fell by 12 s after the transition from REMS to NREMS (P less than 0.05).     

Polyuria and impaired renal blood flow after asphyxia in preterm fetal sheep

Renal impairment is common in preterm infants, often after exposure to hypoxia/asphyxia or other circulatory disturbances. We examined the hypothesis that this association is mediated by reduced renal blood flow (RBF), using a model of asphyxia induced by complete umbilical cord occlusion for 25 min (n = 13) or sham occlusion (n = 6) in chronically instrumented preterm fetal sheep (104 days, term is 147 days). During asphyxia there was a significant fall in RBF and urine output (UO). After asphyxia, RBF transiently recovered, followed within 30 min by a secondary period of hypoperfusion (P < 0.05). This was mediated by increased renal vascular resistance (RVR, P < 0.05); arterial blood pressure was mildly increased in the first 24 h (P < 0.05). RBF relatively normalized between 3 and 24 h, but hypoperfusion developed again from 24 to 60 h (P < 0.05, analysis of covariance). UO significantly increased to a peak of 249% of baseline between 3 and 12 h (P < 0.05), with increased fractional excretion of sodium, peak 10.5 +/- 1.4 vs. 2.6 +/- 0.6% (P < 0.001). Creatinine clearance returned to normal after 2 h; there was a transient reduction at 48 h to 0.32 +/- 0.02 ml.min(-1).g(-1) (vs. 0.45 +/- 0.04, P < 0.05) corresponding with the time of maximal depression of RBF. No renal injury was seen on histological examination at 72 h. In conclusion, severe asphyxia in the preterm fetus was associated with evolving renal tubular dysfunction, as shown by transient polyuria and natriuresis. Despite a prolonged increase in RVR, there was only a modest effect on glomerular function.     

Regional blood flow distribution in fetal sheep with intrauterine growth retardation produced by decreased umbilical placental perfusion

To determine the capacity of the fetus to adapt to chronic O2 deficiency produced by decreased placental perfusion in the early development of growth retardation, we embolized the umbilical placental vascular bed of fetal sheep for a period of 9 days. Fetal umbilical placental embolization decreased arterial O2 content by 39%, decreased total placental blood flow by 33%, and produced a 20% reduction in mean fetal body weight. Neither the combined ventricular output nor the regional blood flow distribution was significantly different between the 8 growth-retarded and 7 normally grown fetuses despite the 39% decrease in fetal arterial O2 content. Thus a 33% reduction in total placental blood flow restricts normal fetal growth, but does not exceed the placental circulatory reserve capacity necessary to maintain normal basal metabolic oxygenation. Because the proportion of combined ventricular output to the placenta at rest is decreased in late IUGR fetuses but not in early IUGR fetuses, despite chronic oxygen deficiency, we conclude that the growth retarded fetus maintains a normal regional blood flow distribution until the placental circulatory reserve capacity is depleted.     

Local blood flow velocities in the carotid body of fetal sheep and newborn lambs

Summary Elastically-suspended microelectrodes were used in the vascularly isolated blood-perfused carotid body of fetal and newborn lambs as well as of 6–7-day-old lambs to measure local blood flow velocities by means of hydrogen clearance. Fetal sheep (n=9) carotid bodies elicited mean local blood velocity values between 0.008 and 0.11 cm·s^–1, whereas newborn lamb carotid bodies (n=7) showed values between 0.008 and 0.067 cm·s^–1 at a perfusion pressure range between 30 and 150 mmHg. The 6–7-day-old lamb carotid bodies (n=5) were characterized by values of 0.003 and 0.049 cm·s^–1 over the same perfusion pressure range. Fetal carotid body values were statistically significantly higher than the values of the 6–7-day-old lamb carotid bodies, whereas the newborn carotid body values showed no significant difference to both other groups. The flow velocity/perfusion pressure relationship peaked at perfusion pressure values between 100 and 150 mmHg in all groups with a reduced steepness in the lamb carotid body. It is concluded that local blood flow velocities in the carotid body are similar to that in other organs, and that after birth local blood flow velocities in the carotid body decrease during the first week of life, probably induced by vasoconstriction, changed blood gas values, and/or increasing shunt flow.Abbreviations significance level - D diffusion coefficient - i.v. intravenous - n number of experiments - PCO ₂ carbon dioxide partial pressure - pH negative logarithm of hydrogen ion concentration - PH ₂ hydrogen partial pressure - Po PH₂ with perfusion - P PH₂ without perfusion - PO ₂ oxygen partial pressure - PP perfusion pressure - r radius     

The effect of rate of heating or cooling prior to heating on tumor and normal tissue microcirculatory blood flow

Single vessel responses to hyperthermia were studied in tumor and normal tissues using a transparent access window chamber. Rates of heating less than or equal to .68 degrees C/minute preserved relatively better vascular function in normal than tumor tissue. A rate of heating of 1.0 degrees C/minute lowered normal tissue statis temperatures so they were no different from tumor. Cooling to 30 degrees C prior to heating slowed normal arteriolar flows to less than 5% of 38 degrees C controls. Heating resulted in increased flow in those vessels, but maximum flows never exceeded 5% of flows achieved in similar vessels which were not cooled first. The implications of this work are that rate of heating and cooling prior to heating can alter normal tissue vascular response to heat in a way that could prove deleterious to maintaining efficient vascular function in that tissue relative to tumor.     

Effects of intravascular infusions of plasma on placental and systemic blood flow in fetal sheep

Six singleton fetal sheep of 118-122 days gestational age were instrumented with flow sensors on the brachiocephalic artery, the postductal aorta, and the common umbilical artery and with arterial and venous intravascular catheters. At 125-131 days of gestation, we started week-long continuous recordings of flows and pressures. After control measures had been obtained, the fetuses were given continuous intravenous infusions of adult sheep plasma at an initial rate of 229 ml/day. After 1 wk of infusion, fetal plasma protein concentrations had increased from 34 to 78 g/l, arterial and venous pressures had increased from 42 to 64 and from 2.7 to 3.7 mmHg, and systemic resistance (exclusive of the coronary bed) had increased from 0.047 to 0.075 mmHg.min(-1).ml(-1), whereas placental resistance had increased from 0.065 to 0.111 mmHg.min(-1).ml(-1). Fetal plasma renin activities fell as early as 1 day after the start of infusion and remained below control (all changes P < 0.05). All flows decreased slightly although these decreases were not statistically significant. Thus the increase in arterial pressure was entirely due to an increase in systemic and placental resistances.     

Relationship between fetal electrocorticographic changes and umbilical blood flow in the near-term sheep fetus

Local blood flow was measured with radioactive microspheres in 9 near-term ewes 2 min into successive high and low voltage electrocortical activity states. In an additional 8 animals the umbilical blood flow was measured using an electromagnetic flow-probe on the common umbilical vein. The microsphere data indicated that the blood flow during low and high voltage electrocortical activity was 185 +/- 22 ml/min per kg of fetus (SEM) and 165 +/- 22 ml/min per kg of fetus (P less than 0.01) respectively. Using the electromagnetic flowprobe the average flow during low and high voltage electrocortical activity was 203 +/- 14 ml/min per kg of fetus and 196 +/- 13 ml/min per kg of fetus (P less than 0.05) respectively. We observed that the decrease in the umbilical blood flow preceded the change from low to high voltage electrocortical activity by approximately 1 min. In that time the flow is significantly lower than it was during the preceding measurements taken during the low voltage electrocortical activity periods. This depression was still significantly lower at 3 min into the high voltage electrocortical activity whereas at 5 min into the high voltage state it was elevated to near average values. We conclude that the umbilical blood flow, on the average, is lower in high voltage states than it is in low voltage states and that this change precedes the switch from low to high voltage electrocortical activity.     

Investigating high-amplitude oscillations in rat tail skin blood flow during core heating and cooling

In a separate paper, we describe high-amplitude oscillations in human skin blood flow (Q˙_sk). Using an open-loop model in rats, we independently modulated and clamped hypothalamic and skin temperatures. Central heating reliably induced these high-amplitude oscillations in tail Q˙_sk, which occurred at 0.41±0.03 Hz spanning 758.1±25.7 ms, and were comprised of high-amplitude peaks (496.8±87.6 AU) arising from a stable baseline (114.1±27.6 AU). Central cooling significantly reduced Q˙_sk, but not the amplitude, the frequency, width or baseline of the oscillations. These observations indicate that such high-amplitude oscillations are not primarily mediated via central thermal state. Instead, we believe these oscillations to be turned on by an elevated skin temperature.     

Effects of naloxone on regional blood flow distribution in canine hemorrhagic shock

The opiate antagonist naloxone increases arterial pressure, maximal left ventricular dp/dt and cardiac output when administered to dogs subjected to hemorrhagic shock. The purpose of this study was to investigate regional blood flow changes associated with naloxone treatment in anesthetized hypovolemic and normovolemic dogs. Hypovolemic dogs (n = 10) were bled over 30 min (t = -30 to t = 0) to a pressure of 45 mm Hg which was maintained for 1 hr. At t = 60, five dogs received naloxone (2 mg/kg + 2 mg/kg X hr), and five received an equal volume of saline. Regional blood flows were determined at t = -30, 45, and 90 min using 15-micron microspheres. Normovolemic dogs (n = 10) were subjected to the same protocol except they were not bled. During hypovolemia, naloxone produced significant increases in myocardial, intestinal, hepatic, and adrenal blood flows whereas saline treatment did not. No significant changes in skin, muscle, fat, pancreatic, renal, or brain flows were detected. The increases in blood flow were not associated with significant changes in vascular resistance. Naloxone had no significant effects on any hemodynamic parameter during normovolemia. The beneficial effects of naloxone in hemorrhagic shock include increased blood flow to vital organs due to increased perfusion pressure which is secondary to improved cardiac performance.     

Metabolic and hormonal responses to cooling the fetal sheep in utero

The metabolic and hormonal effects of cooling 10 fetal sheep in utero (115-142 days of gestation) for 2h were studied. The fetal core temperature fell by 2.81 +/- 0.14 degrees C while the maternal temperature fell 0.86 +/- 0.15 degrees C. This hypothermia caused a significant rise in the fetal and maternal plasma glucose concentrations (P less than 0.001) and a fall in the fetal insulin concentrations (P less than 0.01). The fetal plasma lactate and cortisol concentrations rose rapidly (P less than 0.01) while the growth hormone fell (P less than 0.01) and remained low until cooling ceased when a rapid rebound occurred. There was no significant change in any of the fetal iodothyronines and no elevation of nonesterified free fatty acid concentrations, in contrast to the rapid rise (P less than 0.01) which occurred when newborn lambs were cooled. These observations demonstrate that appropriate glucose, insulin, lactate and cortisol responses to hypothermia have differentiated by 120 days of gestation. However, neither a thyroid hormone response nor an elevation in free fatty acid levels was observed. Thus not all components of the thermogenic response to hypothermia can be demonstrated in the late gestation fetail sheep in utero.